THE EPIDEMIOLOGY OF HIV INFECTIONS: AIDS (Acquired Immuno-deficiency Syndrome) is one of the most deadly diseases which in the recent times has struck humans and has reached epidemic proportions. It is estimated that 5 to 10 million people are infected with HIV worldwide. AIDS has been reported in more than 123 countries.
The Center for Disease Control (CDC) estimates that the number of HIV-infected individuals in the United States is about 1 to 1.5 million. The number of AIDS cases reported as of November, 1988 is 77,900. 60% all AIDS patients die within 11/2 years of diagnosis and upwards of 90% within 3 years. CDC data show that within 7 years 35% of all infected people will progress to full-blown AIDS and another 45% will progress to ARC (AIDS-related complex) or have lymphodenopathy or other signs of immunological disorders. Only 20% will remain asymptomatic, and these too will probably become ill in time.
The geographical origin of the HIV infections and AIDS is not exactly known. However, it is believed that the disease came to North America and Europe from Africa. The green monkey in Africa harbors the virus but it seems that he does not develop the disease. Some native Africans use the monkey as pets and for food. It is possible that the virus went through mutations and became patheogenic for man.
The first cases of AIDS were reported in 1981. It emerged as a mysterious syndrome, the etiology of which was unknown. The syndrome for a while inflicted male homosexuals, then it was seen in drug addicts who shared needles, and later it was seen in other risk groups.
THE HUMAN IMMUNODEFICIENCY VIRUS (HIV): Montagnier and his group at the Pasteur Institute of Paris, in 1983 published their work in Science on the discovery of a retrovirus belonging to the family of human T-cell leukemia viruses (HTLV) which had previously been reported. The new retrovirus was isolated from the cervical lymphodenopathy of a patient with Pre-AIDS symptoms. The virus was called LAV (Lymphodenopathy Associated Virus). The virus was a typical type C-RNA tumor virus; it was found to bud from the cell membrane, to prefer magnesium for reverse transcriptase activity, and to have an internal antigen (p. 25) similar to HTLV (p. 24). The virus was transmitted into cord blood lymphocytes and the virus produced by these cells was similar to the original isolate. They concluded that this virus as well as the previous HTLV isolates belonged to a general family of T-lymphotropic retroviruses, and that they might be involved in several pathological syndromes including AIDS.
Gallo and his group at the National Cancer Institute reported their work, also in Science, in 1984 on the isolation of cytopathic retroviruses from 48 patients with AIDS and at risk for AIDS. These retroviruses also appeared to belong to the HTLV family but they differed from them in morphological, biological and immunological characteristics. They concluded that these retroviruses, now called HTLV-III, might be the primary cause of AIDS.
These two independent findings confirmed each other. It was then widely accepted that the etiologic virus of AIDS was the newly discovered retrovirus. The retrovirus has now been called Human Immunodeficiency Virus (HIV).
THE BIOLOGY OF HIV: The virus is an RNA virus and it has the enzyme reverse transcriptase which enables it to make a DNA copy of the viral RNA. The virus has an outer envelope and a dense cylindrical core containing RNA genome. The envelope consists of a lipid membrane with protruding spikes which are coated with glycoproteins. The glycoproteins contain different sugar molecules, some of which appear to be constant, but some may be variable. It is though that it is the variability of these sugar molecules that eludes the body's immune system in detecting the virus particles. Genes that code for structural components of HIV include the gag gene which codes for core, the env gene which codes for envelope proteins, and the pol gene which encodes viral reverse transcriptase. The gag, pol and env genes are common to all retroviruses. The diameter of the virus is 100-120 nm and it is produced in high numbers from infected cells by budding from the cell membrane in culture.
The virus exists in the blood circulation of the patient in two forms: As cell-free virus or mature virion having a lipid envelope, and as cell-associated virus or replicating virus in the infected cells (T-4 lymphocytes, monocytemacrophages). The virus is essentially an intracellular parasite and in order to survive and perpetuate itself it has to penetrate and infect the host cells. The lipid envelope with its glycoprotein spikes provide the means for penetrating and infecting the white cells. The virus will replicate inside the infected cells and will produce mature virions with lipid envelope and glycoprotein spikes, budding from the membrane of the infected cell. These mature virions in turn will penetrate and infect the new and healthy cells as they are released from the hematopoietic system, and the vicious cycle will go on.
THE T-4 MOLECULE AND HIV: Laboratory studies of AIDS patients have revealed a depletion of T-4 helper lymphocytes in their peripheral blood. This results in an overall decrease of lymphocytes as well as inversion of T-4 helper lymphocytes to T-8 suppressor lymphocytes. The function of T-4 receptor is not exactly known, but it is know that the receptor associates closely with a type of cell antigen that must be present on an antigen-presenting cell in order for the T-4 lymphocytes to interact with it and recognize a foreign antigen. HIV replicates in T-4+ lymphocytes and apparently not in other types of lymphocytes.
The target host cells invaded by HIV known today include T-4 lymphocytes, monocytes, macrophages and colorectal cells (lymphoid tissues). All of these cells contain messenger RNA for T-4 molecule and express the T-4 protein on the cell surface. The T-4 gene is also expressed on cells distributed throughout the neuraxis. A recent series of experiments has demonstrated that cells that do not normally have the T-4 molecule on their surface and are resistant to HIV infection in vitro become capable of being infected after genetic engineering and expressing the T-4 antigen on their surface. Thus, the T-4 molecule appears to be necessary for HIV infection of human cells.
Other studies showed viral RNA, by in situ hybridization, in the brain tissue. Culture of brain biopsy of a seropositive patient with progressive dementia showed monocytoid cells which by electron microscopy revealed mature virions. Viral RNA was detected in the brain tissues of 2 patients with AIDS encephalopathy. In an infant with Lymphocytic Interstitial Pneumonia, cells were found in the lung tissue to be positive for HTLV-III RNA. It is thought that the infected monocyte-macrophages may carry the virus to these organs.
As to how many years after the patient's exposure to HIV, it will take for the virus to be carried to these organs by the monocyte-macrophages, and as to whether or not the monocyte-macrophages will eventually carry the virus to these organs in every infected patient, is not known. It is also not certain as to whether the virus particles found in these organs are latent or possibly some of these virus particles may be replicating at times, and thereby re-stocking the peripheral blood with mature viruses.
Most persons having antibodies to the virus appear to be infectious, i.e. the virus can be isolated from their peripheral blood lymphocytes. A patient may be infected, i.e. may carry the virus in T-4 lymphocytes and blood, for many years and not be symptomatic.
CLINICAL CRITERIA OF PRE-AIDS AND AIDS: Overt AIDS (Acquired Immuno-deficiency Syndrome) is preceded by a period of prodrome that may last for many months (ARC or AIDS-related complex). The patient develops fever, weight loss, malaise, lymphodenopathy and recurrent chronic diarrhea. The full-blown AIDS is characterized by weight loss, fever, severe headache, neck stiffness, arthralgia and skin rash. The patient develops opportunistic infections including: Pneumocystis carinii pneumonia, cytomegalovirus infections, toxoplasmosis, oral condidiasis, and intestinal cryptococcosis with resultant vitamin B.sup.12 deficiency. Herpes simplex virus (HSV) infections are common in patients with AIDS and may be severe and persistent requiring intravenous therapy by acyclovir. Other findings include: Gradual gait disturbance, paraplegia, spinal cord degeneration, and chronic dementia.
SUSCEPTIBLE GROUPS: Patients that have been described with AIDS: Homosexual males, intravenous drug users, patients with hemophilia treated with transfusion of blood or blood products, female partners of males with AIDS, infants born of mothers having AIDS. No one is known not to be at risk for AIDS.
LABORATORY STUDIES: A number of laboratory tests have been developed to detect the serum antibodies of HIV antigens. Some of these tests are done at special clinical laboratories and some are mainly used for research.
The immunodeficiency is manifested by skin test anergy and decrease in T-4 helper lymphocytes and inversion of T-helper to T-suppressor ratios in the peripheral blood. Cultures of blood are positive for HIV. If there is involvement of the central nervous system, cultures of cerebrospinal fluid will also be positive for HIV.
Enzyme-linked immunosorbent assays (ELISA) to detect antibodily to Human Immonodeficiency Virus (HIV) are being used for screening blood products, for clinical purposes and for epidemiologic studies. Confirmation is accomplished by a second assay such as the Western blot test.
In Western blot, HIV antigens are separated electrophoretically and the ELISA-reactive serum is tested against all of these separated antigens. Clear reactivity to certain virus antigens demonstrates true infection with HIV.
Like other serologic tests, the ELISA indicates the occurrence of past infection. However, individuals with confirmed test results are presumed to be currently infected and capable of transmitting infection through blood or sexual contact.
Seroconversion or the presence of detectable antibody levels is seen at 4 to 12 weeks after infection occurs. However, prolonged seronegativity up to a year or even longer has been reported.
The indirect immunofluorescence assay (IFA) is another confirmatory test. With this test serum reacts with infected cells from tissue culture. Antibodies to HIV antigens attach to many sites within the infected cells, the attached antibody is detected with fluorescent-labeled goat antihuman globulin and read under a fluorescent microscope.
INACTIVATION OF HTLV-III/LAV IN LABORATORY SETTING: A number of studies have been recently published on the effects of physical and chemical agents on HTLV-III/LAV. One of these studies showed that the virus titer could be reduced by 1 long (tenfold) at 60.degree. C. for 32 minutes. Another study found that after exposure up to 2.5.times.10.sup.5 rad gamma rays the virus was still infectious for human lymphocytes. It should be noted that the amount used for food material is generally at least 10 times lower than this. To inactivate the virus a dose higher than 2.5.times.10.sup.5 rad would be needed. It was also found that LAV reverse transcriptase activity was slightly sensitive to UV radiation, the enzyme activity decreasing as a function of the delivered dose. No infectious virus was detected in their infectivity assay in samples irradiated with more than 5.times.10.sup.5 J/m.
Another study found that 1% gluteraldehyde or 25% ethanol is sufficient to disinfect medical instruments. A recent study published in 1987 demonstrated that viral infectivity of HTLV-III/LAV was undetectable and was reduced more than 7 log.sub.10 TCIP.sub.50 within one minute with copious amounts of 0.5% sodium hypochlorite, 70% alcohol, or 0.5% nonidet-P40, and within ten minutes with 0.08% quaternary ammonium chloride or with a 1:1 mixture of acetone-alcohol.
The authors used these results to provide a rational basis to prevent the accidental spread of HTLV-III/LAV in the laboratory or clinical setting. The authors did not consider these tests or the results of these tests to provide a method or means with which the treatment of HTLV-III/LAV infections of a patient could be effected.